Cocaine abuse affects approximately 1.7 million individuals nationwide per year and is characterized by patterns of excessive drug seeking and taking, including a preoccupation with obtaining the drug, repetitive seeking and taking of the drug, and a loss of control over drug intake (American Psychiatric Association, 2000). Experimental animals exhibit similar compulsive behaviors when exposed to extended access to cocaine self- administration. Compulsivity in rodent drug addiction models is characterized by excessive patterns of drug seeking and taking behavior, including escalation of drug intake, elevated progressive ratio breakpoints, drug seeking in the face of punishment, elevation in brain reward thresholds during abstinence from the drug, and the reinstatement of cocaine seeking following extinction (Wee et al., 2007a; Ahmed et al., 2002). Compulsive- like cocaine taking, in part, occurs through neuroadaptations of brain stress systems that mediate negative emotional states implicated in motivational processes required for maintaining the dependent drug state (for review, see Koob, 2008). In addition, it is well documented within the literature that stress systems play a significant role in the reinstatement of drug seeking following extinction, a model of drug relapse (for reviews, Shaham et al, 2003; Lu et al, 2003). Recently, the lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug taking and the reinstatement of drug seeking (for review, see Boutrel et al; 2010). Interestingly, limited evidence suggests HCRT may be driving drug seeking through activation of specific brain regions implicated in stress system dysfunction, including dopaminergic regions of the mesocorticolimbic system and CRF in the extended amygdala (Boutrel et al 2005; Hata et al., 2011). The role of HCRT in the emergence and persistence of compulsive behaviors associated with cocaine addiction has yet to be fully elucidated. Thus, the goal of the current research proposal is to characterize the role of HCRT in the mediation of increased progressive ratio breakpoints, punishment-resistant responding for drug and reinstatement of drug seeking following extinction. To achieve this goal, we will use an extended access model of addiction and HCRT-1 receptor antagonist and/or viral-vector mediated HCRT knockdown to determine the degree to which HCRT plays a role in compulsive drug seeking behavior in escalated animals and stress- and cue-induced reinstatement of cocaine seeking following extinction. Finally, Western blot analyses will be used to determine the role of HCRT in the biochemical neuroadapations within the ventral tegmental area and extended amygdala following escalated cocaine intake.